tbuckley/cabot-search huggingface dataset:
Relationship between IL-1β and IL-8 serum concentrations in patients with metastatic melanoma taking checkpoint inhibitors.
Authors: Rashida Orlova, Anna Malkova, Natalia V. Zhukova, Ekaterina Kaledina, Alexandra Demchenkova, Polina Naymushina, Vladimir Sharoyko
Journal: Journal of Clinical Oncology (2022)

e21510 Background: Melanoma is a disease that is most often treated with immune checkpoint inhibitors (ICI). The principle mechanism of ICI is based on the activation of the antitumor immune response. This therapy is not effective in all patients, which may be due to the immunosuppressive effect of tumor microenvironment (TME). IL-1β is one of the most important participants in the TME, however, it is difficult to determine it in blood serum, in contrast to IL-8, the synthesis of which is induced by IL-1β. The study aims to determine the relationship between IL-1β and IL-8 in patients with metastatic (mts) melanoma and to reveal their diagnostic significance. Methods: The study involved 28 patients (pts) with mts melanoma taking ICI. The level of IL-1β and IL-8 in blood serum was determined using the ELISA method. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC, Wilcoxon matched-pairs signed rank test, Spearman statistical analysis. Results: IL-1β was detected in 35.5% (11/31) of patients before therapy, while an elevated level was recorded in only one patient. IL-8 was found in all patients, an elevated level before therapy was observed in 64.5% (20/31) of cases, after 2-3 months - in 35.5% (11/31). During ICI therapy, a statistically significant decrease in the concentration of IL-1β (p = 0.0498) and IL-8 (p = 0.0002) were observed. In the presence of IL-1β, the level of IL-8 was statistically higher (139.6±65.26 pg/ml), p = 0.024, while a mean positive correlation was found between IL-1β and IL-8 concentrations (R = 0.6469, p = 0.035). According to ROC analysis (Area = 0.76), with an increase in the concentration of IL-8 more than 42.31 pg/ml with a diagnostic sensitivity of 66.67% and a specificity of 90.00%, it can be assumed that the level of IL-1β will be detected in the patient (p = 0.025). Conclusions: According to the study, with an IL-8 concentration of more than 42.31 pg/ml in patients with mts melanoma, the presence of IL-1β in the blood serum can be expected. At the same time, the level of IL-8 correlated with the level of IL-1β. It can be assumed that high level of IL-8 may indicate the overexpression IL-1β in TME and it`s high activity, which may be associated with the possible risk of low ICI efficacy.
Largest evaluation of acquired resistance to sotorasib in <i>KRAS</i> p.G12C-mutated non–small cell lung cancer (NSCLC) and colorectal cancer (CRC): Plasma biomarker analysis of CodeBreaK100.
Authors: Bob T. Li, Vamsidhar Velcheti, Timothy Jay Price, David S. Hong, Marwan Fakih, Dong-Wan Kim, Gerald Steven Falchook, Jean-Pierre Delord, Grace K. Dy, Suresh S. Ramalingam, John H Strickler, Takayasu Kurata, Juergen Wolf, Adrian G. Sacher, Alfredo Addeo, Hans Prenen, Antreas Hindoyan, Abraham Anderson, Agnes Ang, Ferdinandos Skoulidis
Journal: Journal of Clinical Oncology (2022)

102 Background: Sotorasib, a specific, irreversible KRAS G12C inhibitor, has been approved in multiple countries for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapy based on the global phase 1/2 CodeBreaK100 trial. Here we describe putative mechanisms of acquired resistance to sotorasib from the largest single dataset evaluated to-date. Methods: Patients with advanced KRAS p.G12C-mutated NSCLC or CRC from the CodeBreaK100 Ph1/2 trial who received sotorasib monotherapy at 960 mg once daily were analyzed for efficacy. Primary endpoint was objective response rate (ORR) assessed by central review. To investigate biomarkers of resistance to sotorasib, an exploratory endpoint was defined to examine acquired genomic alterations at disease progression. Plasma samples collected at baseline and progression were analyzed for genomic alterations with the 23-gene Resolution Bioscience ctDx Lung test for NSCLC and the 74-gene Guardant 360 ctDNA test for CRC. Acquired genomic alterations were defined by their absence at baseline and presence at progression. Results: In 174 pts with NSCLC and 91 pts with CRC-treated with sotorasib, the ORR were 41% and 12% respectively. Median progression-free survival and median overall survival were 6.3 months (mos) and 12.5 mos for NSCLC pts and 4.2 mos and 13.4 mos for CRC pts (median follow-up: 22.5 mos NSCLC; 12.5 mos CRC). A total of 67 NSCLC pts and 45 CRC pts had a plasma sample sequenced both at baseline and at progression. At least one new acquired genomic alteration at progression was detected in 19 (28%) NSCLC pts and in 33 (73%) CRC pts (Table). The acquired genomic alterations were heterogeneous in both NSCLC and CRC, with variants detected across multiple genes and pathways. The most prevalent putative pathway of resistance in both NSCLC and CRC was the receptor tyrosine kinase (RTK) pathway. Secondary RAS alterations occurred more frequently in CRC versus NSCLC pts (16% vs. 3%). Conclusions: Based on the largest descriptive dataset to-date, diverse mechanisms of acquired resistance occur in KRAS p.G12C-mutated NSCLC and CRC pts treated with sotorasib. New RTK pathway alterations frequently emerged at progression, highlighting the potential role for combining sotorasib with upstream inhibitors of RTK, such as SHP2 or EGFR inhibitors. Serial plasma DNA analysis revealed acquired resistance patterns that support the development of KRAS G12C inhibitor combination therapies. Clinical trial information: NCT03600883. [Table: see text]
Whole brain radiotherapy and association with rapid brain aging as determined by anatomic surface morphology.
Authors: Nikhil Rammohan, Alexander Ho, Tim J. Kruser, Pierre Besson, S Kathleen Bandt
Journal: Journal of Clinical Oncology (2022)

e14007 Background: Brain metastases are the most common intracranial tumors in adults and are associated with significant morbidity and mortality. Whole brain radiotherapy (WBRT) is used frequently in patients for palliation, but can result in neurocognitive deficits. While dose-dependent injury to individual areas such as the hippocampus have been demonstrated, global structural changes after WBRT remain to be studied. Our group previously published a magnetic resonance imaging (MRI) deep learning model based on anatomic brain surface morphology to accurately predict brain age in healthy subjects. We now report the effect of WBRT on aging pace of the irradiated brain. Methods: We studied patients with brain metastases and examined MRI brain anatomic surface data before and after WBRT. We implemented a graph convolutional neural network model to estimate patient’s brain age. We further developed a mixed-effects linear model to compare age of whole brain and substructures before and after WBRT, written as follows: Δ Age = c + β(Δ Scan ) + 1|patient_ID; where for each patient, Δ Age = [(model_predicted_age_at_follow up – actual_age_at_follow up) – (model_predicted_age_pre_treatment – actual_age_pre_treatment)], Δ Scan = time interval between pre-and post-treatment MRI scans, β = aging coefficient (β =0 corresponds to normal aging), and c = intercept (model_predicted_age_pre_treatment – actual_age_pre_treatment). Results: 56 patients were analyzed. The median age was 62 (range 32 – 85). Two-thirds of patients were female. Primary organ site was breast or lung in 87% of cases and 77% of patients had five or more metastases. Median radiation dose was 30Gy (range 25 – 37.5Gy). Results of aging analysis are presented in Table. Small c values demonstrate that model accurately predicted age pre-treatment. The whole brain and substructures underwent rapid aging compared to normal aging pace (β&gt;&gt;0). Based on median follow up of 6.3 months, the whole brain aged approximately 4.94 years, the cortex aged approximately 4.53 years, the subcortical structures aged approximately 5.94 years, and the hippocampus aged approximately 5.17 years. Conclusions: Our findings suggest that WBRT causes the brain and its substructures to age at a pace of 9-11x of the normal aging pace, mirroring deficits in long-term neurocognition seen post-treatment. Given post-treatment aging pace and increasing survival for many patients with brain metastases, WBRT needs to be used judiciously. [Table: see text]
Trajectory of aging following diagnosis of cancer.
Authors: Morgan Simons, Chen Lyu, Iman Osman, Hua Zhong
Journal: Journal of Clinical Oncology (2022)

12087 Background: Aging is a nebulous concept with several definitions, but they all generally include physical and cognitive decline in function as a key component. We hypothesized that following cancer diagnosis, patients decline in physical and cognitive function would correspond with accelerated and/or accentuated aging trajectories. The magnitude of the functional changes could inform strategies to minimize impact of cancer diagnosis on trajectory of aging. Methods: We analyzed 32,935 participants &gt;50 years enrolled between 1995-2018 in the Health and Retirement Study (HRS), a population-based, biennial longitudinal health interview survey of older adults in the United States. We assessed the changes in physical and cognitive function among cancer patients controlling for their pre-cancer trajectories and comparing it with aged population with no cancer diagnosis as control. The primary outcomes were change in physical function (Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL): range 0–11) and global cognitive function (Telephone Interview for Cognitive Status (TICS): range 0–27). The secondary outcome was change in self-rated health (SRH: range 1-5). We estimated the effect of acute change based on the immediate post-cancer outcome measurements compared to the trajectories before cancer; and the long-term effect as the per-year change in outcome decline post cancer compared to aging of cancer-free respondents adjusting covariates by linear mixed models. Results: 5,101 developed incident cancer: 1,514 in the 50-64 age group, 1,901 in the 65-74 age group, and 1,686 in the 75+ age group. 27,834 participants were cancer-free throughout. Cancer was associated with acute declines in physical function (0.06 [0.01– 0.10] and 0.25 [0.14– 0.36] points), cognitive function (0.22 [0.04–0.39] and 0.24 [0.01– 0.46] points), and SRH (0.19 [0.14–0.23] and 0.22 [0.12–0.33] points) for age of onset groups 50- and 75+ respectively. Moreover, participants with cancer demonstrated accelerated decline in physical function (0.02 [0.01–0.03], and 0.06 [0.05–0.07] points per year faster for 50-74 and 75+ age-of-onset groups respectively) compared to cancer-free participants, but not in cognitive and SRH. Lung, colorectal &amp; breast cancer were associated with the highest acute and accelerated decline in functions, while prostate cancer was associated with moderate and insignificant decline. Conclusions: Using 24 years of nationally representative longitudinal data, this study provides, for the first time, evidence for the heterogeneous aging trajectories of cancer patients across varying age-of-onset and cancer types. Our results supported an accelerated aging trajectory of physical function with increased acceleration with increasing age-of-onset compared to the non-cancer population. It also provides evidence for accentuated aging trajectories of cognitive function and self-rated health.
Homologous recombination deficiency is linked to shorter survival expectancy in late-stage colorectal cancer.
Authors: Jianxia Li, Jianwei Zhang, Dandan Dai, Huabin Hu, Yue Cai, Jiayu Ling, Xuan Zhang, Yanhong Deng
Journal: Journal of Clinical Oncology (2022)

e15576 Background: Colorectal cancer patients with high-level microsatellite instability (MSI-H) benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all colorectal cancer patients. The remaining patients are still lack of effective therapeutic biomarkers to predict their prognosis. For patients in late stage without optimal treatment, it is essential to find novel biomarkers which can be used to select appropriate therapies and therefore improve patients’ overall survival. Methods: We used whole-exome sequencing (WES) to analyze 99 colorectal cancer samples. The patients were further classified into different groups based on their microsatellite status (MS), homologous recombination deficiency (HRD) score, as well as other clinical characteristics, which might associate with clinical outcomes. Afterward, survival analysis and stratification analysis were performed to explore the significant prognosis and predictive indicators in each group. Additionally, we assessed somatic genomic lesions, copy number aberrations, and mutational pathway, and analyzed the differential genetic patterns in distinct clinical benefit groups. Results: The multivariate Cox regression analysis proved that HRD score was associated with significant OS (HR 0.19, 95% CI 0.12-0.94, p = 0.002), suggesting HRD are prognostic factors for late stage CRC. Therefore, the patients were classified into two subgroups according to the value of the HRD scores (HRD-high vs HRD-low). For comparison, the prominent difference was observed in the somatic mutations and copy number alterations (SCNAs). Our results showed TP53 (78%) , APC (50%) and KRAS (41%) as the most frequently cancer-related mutations in CRC, consistent with previous studies. In patients with MSS group, the SMAD4 mutation was occurred frequently (p &lt; 0.01), as well as a distinctive pattern of chromosomal amplification in HRD-high group patients. However, in patients with MSI group, none significant mutations were observed in HRD-high and HRD-low groups. Conclusions: We integrated HRD statue as prognosis and predictive factors for late stage CRC as determined using WES sequencing. Moreover, we also provide a comprehensive differential genetic pattern in stratification of CRC patients, as well as underscore an importance of combining strategy for molecular diagnosis of CRC.
Tremelimumab (day 1 only) and durvalumab in combination with transarterial chemoemobilization (TACE) in patients with hepatocellular carcinoma (HCC).
Authors: Jemma Buchalter, Niamh Evans, Iseult Browne, Colm Mac Eochagain, Calvin Flynn, Hailey Kathryn Carroll, Marie Galligan, Michele Bourke, Amy Lester-Grant, Katherine Hoey, Ronan Ryan, Colin P Cantwell, Jeffrey McCann, Ray McDermott, Ross MacNicholas, Austin G Duffy
Journal: Journal of Clinical Oncology (2022)

e16175 Background: TACE induces a peripheral anti-tumor immune response, which may be amplified by immune checkpoint inhibitors (ICI). Combining TACE with dual ICI therapy has been shown to be safe and feasible. Recent data has suggested that Day-1 only anti-CTLA4 dosing, at a higher level of 300mg, could lead to a stronger immune response, and drive a greater expansion than lower dose regimens, whilst maintaining a tolerable safety profile. This novel schedule has not previously been combined with TACE. Methods: Patients with HCC (Childs Pugh A/B7, Barcelona clinic liver cancer stage B/C; ECOG 0/1; sorafenib-naive or experienced) were enrolled in a pilot study of tremelimumab at 2 dose levels (DL1: 75mg IV q4-weekly x 4 and DL2: 300mg IV D1 only) in combination with durvalumab (1500mg IV q-28d) and TACE (D36 +/- 96 hours) until progression of disease (per irRECIST) or off-study criteria. Peripheral immune monitoring was performed and tumor biopsies were obtained at time of TACE. Results: 13 patients enrolled on study; N = 3 at DL1 and N = 10 at DL2. M:F 10:3. Median age 70 (65-74). BCLC B/C 4/9. Extrahepatic disease 6/7. Aetiology: NASH (N = 3), alcohol-related disease (N = 1), HCV (N = 2), hemochromatosis (N = 1), unknown (N = 6). 1 pt discontinued due to G3 colitis. All patients evaluable for response with 2/10 pts on DL2 experiencing PR (at 8 weeks) and overall 7/13 SD and 1/13 PD as best response. Updated PFS and OS data to be presented. Conclusions: Tremelimumab (Day 1 only) and Durvalumab in combination with TACE is safe and feasible in patients with HCC. Follow-up is ongoing and full safety and efficacy data will be presented. Clinical trial information: 2019-002767-98.
LGG-07. Novel CRISPR/Cas9 induced KIAA1549:BRAF fusion model for preclinical studies of pediatric gliomas
Authors: Krupesh Patel, Guisheng Zhao, Shih-Ming Huang, Triantafyllia Karakousi, Theodore Nicolaides, Thales Papagiannakopoulos
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Pediatric Low Grade Gliomas (pLGG) are the most common group of central nervous system (CNS) tumors in children and cause significant morbidities. Pilocytic astrocytoma (PA) is the most frequent pLGG. KIAA1549:BRAF fusion is a well-established oncogenic driver in PA. Oncogene induced senescence (OIS) has prevented establishing PA cultures for in vitro and in vivo studies. Here we look at a novel NIH-3T3 fibroblast model harboring KIAA1549:BRAF fusion gene via CRISPR/Cas9 somatic genome engineering technology. OBJECTIVES: Establishing that the CRISPR/Cas9 edited NIH-3T3 fibroblast model with the KIAA1549:BRAF fusion is valuable for in vitro and in vivo studies without early OIS. DESIGN/METHOD: CRISPR/Cas9 editing technology was used to establish a KIAA1549:BRAF fusion positive cell model. This cell model was studied in vitro with MEK inhibitor cobimetinib (GDC-0973) and using WST-1 viability assay, clonogenic assay, senescence β-galactosidase staining, and western blot. In vivo murine models with subcutaneous fusion positive NIH-3T3 fibroblast tumors were treated with GDC-0973. Survival studies and tissue studies were subsequently done. RESULTS: A fusion positive NIH-3T3 fibroblast model was successfully established. Increased BRAF cDNA expression and higher levels of p-ERK were observed. In vitro studies showed decreased viability with GDC-0973. Clonogenic assay showed qualitative and quantitative decreases in viable cells. P-ERK target inhibition was established without induction of senescence. In vivo studies demonstrated successful subcutaneous tumor implantation, therapy efficacy, and target inhibition. CONCLUSION: CNS tumors, most commonly pLGG, in children cause significant morbidities. KIAA1549:BRAF fusion is an oncogenic driver in PA. In vitro and in vivo studies are important for pre-clinical models. OIS has prevented establishing adequate fusion positive animal cell models. Here we have demonstrated a successful CRISPR/Cas9 edited fusion positive NIH-3T3 fibroblast model.
HGG-03. PEDIATRIC BITHALAMIC GLIOMA H3K27M NEGATIVE AND EGFR POSITIVE: A DISTINCT ENTITY WITH POTENTIAL SENSIBILITY TO EGFR INHIBITORS
Authors: Marta Cortes Hernandez, Guiomar Gutierrez Schiaffino, Silvia Torrejon Almeida, Sara Iglesias MoroñO, Bernardo Weil Lara, Maria Isabel Martinez Leon, Martina Alvarez
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Brain tumors are the most common solid tumors of childhood and optimal therapeutic strategies for many subtypes remain unknown. Bithalamic gliomas, in contrast with unilateral, have frequent mutations in the EGFR oncogene and only rare Histone H3 mutation. These EGFR mutations are small inframe insertions within exon 20 or missense mutations within exon 7 and occur in absence of gene amplification. CASE REPORT: A previously healthy 10-years-old boy with adequate neuropsychomotor development was admitted with a 5-day-long headache. A brain magnetic resonance imaging (MRI) showed an expansive midline lesion with thalamic extension. The tumor showed no diffusion restriction or contrast enhancement. An endoscopic septostomy and biopsy were performed.The histopahotology showed a diffused astrocytoma grade II. The immunohistochemistry was negative for IDH1 and 2, BRAF mutation, P53 and H3K27M. Next generation sequencing (NGS) ruled out histone H3K27M mutation and showed EGFR mutation in exon 7. The patient experimented clinical and radiological disease progression in a few weeks, confirming the high grade glioma despite the histopahological diagnosis.He received radiotherapy (Total dose 54Gy) and after radiation he started target therapy with Osimertinib, a third generation tirosin kinase inhibitor. As a toxiticy, he experienced neutropenia Grade 2. Disease evaluation performed after 2 cycles showed stable disease. DISCUSSION: Our case report represents a distintc molecular class of pediatric-type bithalamic glioma characterized by EGFR alteration and absence of H3K27M mutation. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
Impact of structured debriefing sessions on residents rotating on inpatient oncology.
Authors: Hina Dalal, Sarah Thilges, Patricia B. Mumby, Nazzara Chervinko, Ellen Girardi, Shelly S. Lo
Journal: Journal of Clinical Oncology (2022)

11018 Background: Participating in end-of-life (EOL) care may lead to physician distress and burnout. Residents rotating on inpatient oncology services often care for patients and families nearing the EOL. There is no standardized resident training for EOL care nor are there standardized methods to assist with resultant emotional distress. Studies have demonstrated that residents on hematology/oncology rotations experience acute empathy decline, which can lead to cynicism and depersonalization, contributing to burnout (McFarland, 2016). Our objective was to prospectively evaluate the impact of a structured debriefing session during a 4-week inpatient oncology rotation on residents' concerns about death and rotation satisfaction. Methods: During week 1, residents completed a 10-item Concerns about Dying (CAD) instrument (Mozer, 2004). During week 3, residents participated in a structured 60-minute debriefing session with a clinical psychologist or licensed social worker specializing in hematology-oncology. During week 4, residents completed the CAD and an end-of-rotation self-assessment. Results: 58 individual residents rotated through inpatient oncology at Loyola University Medical Center from 7/2020 – 1/2022. 15 residents were excluded as they did not complete both the pre and post surveys. Trainees had a lower CAD score at the end of their oncology rotation, indicating a more positive attitude towards death and dying. PGY1s had the greatest decrease in CAD score over 4 weeks. Anxiety (70%), relief (70%), satisfaction/pride (63%) and sadness (58%) were the most common emotions residents felt while providing EOL care. 42/43 (98%) residents were comfortable discussing EOL topics with a licensed counselor and 40/43 (93%) felt the debriefing had a positive impact on their rotation. 38/43 residents (88%) believed the debriefing reduced sentiments of cynicism and dissatisfaction caused by emotional distress related to EOL care. Conclusions: Resident concerns about death decreased during a 4-week inpatient oncology rotation in which a structured debriefing program occurred during week 3. Although the study protocol does not provide causation, it suggests the debriefing allowed residents to reflect on EOL care and enhance their ability to cope with distress. The favorable feedback from this pilot led to a permanent curricular change for the inpatient oncology rotation. Strategies to assess and manage emotional strain among residents providing EOL care remain limited and warrant further investigation.[Table: see text]